Cystic fibrosis (CF) is among the most prevalent, lethal diseases of genetic origin. Approximately 30,000 children and adults are affected in the United States alone. In this disease, abnormal ion transport across the respiratory epithelia leads to dehydrated, viscous and poorly-cleared airway secretions that contribute to chronic infection of the airways and early death. Knowles, Clin. Chest. Med. 11, 75 (1986). Chronic obstructive pulmonary disease (COPD) affects 10 to 14 million individuals in the United States and is also characterized by mucus accumulation in airway lumens and metaplasia of mucus secreting goblet cells. See, e.g. Celli et al., Am J Respir Crit Care Med 152, S177-S210 (1995). Hence, there is a need to develop new ways to treat cystic fibrosis and chronic obstructive pulmonary disease.
In cystic fibrosis several functions of airway epithelia are abnormal, and deficiencies in both transport Cl− and Na+ absorption are well documented. See, e.g. Knowles et al., Science 221, 1067 (1983); Knowles et al., J. Clint. Invest. 71, 1410 (1983). It would be extremely useful to provide a mouse model of cystic fibrosis and chronic obstructive pulmonary disease so that treatment options to improve mucus clearance in vivo could be more vigorously pursued. Unfortunately, prior efforts to develop a mouse model of cystic fibrosis produced animals that did not develop spontaneous lung disease. See, e.g., B. Grubb and R. Boucher, Physiological Reviews 79, S193-S214 (1999). Accordingly, there is a need for new approaches to solving the problem of providing an animal model for cystic fibrosis or chronic obstructive pulmonary disease.